Drug delivery device

ABSTRACT

A drug delivery device having a housing containing a gas generator controlled by an electronic controller. The gas generator generates gas into a reciprocable chamber, whereby reciprocation of the chamber causes a lever to reciprocate a pawl, and this action causes a ratchet to The device may also be provided with manually control for delivering a bolus dose Of drug when necessary.

This invention relates to drug delivery devices, and in particular toportable devices designed to be carried by a patient during normalactivities.

BACKGROUND OF THE INVENTION

A number of drug delivery devices are known in which medicament isdriven from a reservoir, under the action of a driving mechanism,through a needle and into the skin of a patient. A problem with knowndevices is that the delivery rate accuracy suffers when the volume ofdrug is small. Such inaccuracies arise in many cases from the drivingmechanisms employed which give rise to variations in delivery rates. Forexample, where a gas is generated to drive a plunger in a cartridge orvial, the volume of gas depends in part on the temperature of theenvironment. The variation in volume will also depend on the totalamount of gas already present in the chamber.

The reason that gas generation is preferred over mechanical drivingmechanisms is that the design of gas generating cells, such aselectrolytic cells' is extremely simple when compared to mechanicalequivalents, and this provides significant advantages in terms ofreliability and cost-effectiveness. Systems are known in which amechanically driven ratchet is used to incrementally deliver fixedamounts of medicament, but such systems can be expensive to manufacture.In particular, the accuracy of delivery of small amounts of drug dependson the manufacturing tolerances of the ratchet mechanism. Formass-produced, moulded, cut or pressed ratchets, the tolerances may notbe sufficiently accurate to deliver the required small volumes, whichmeans that more expensive manufacturing techniques are required toobtain the necessary tolerances. Such considerations are particularlyimportant if the devices are intended to be disposable, in which case alow unit cost is required without compromising accuracy or reliabilityor system performance.

A problem with gas driven mechanisms, however, is that it is extremelydifficult to ensure that a gas chamber is leakproof without takingelaborate manufacturing and quality control precautions. Even if a leakis minor and relatively slow, this poses a real problem when themechanism is supposed to accurately deliver small volumes over extendedtimespans. Thus, for gas generation systems, it is preferred to design asystem that is leak free (which is costly and typically more complex) orprovide a system that functions accurately in spite of minor orrelatively slow leaks. In the alternative, gas generation may not besuitable for lower delivery rates. As mentioned above, mechanicalequivalents having the required precision (e.g. clockwork mechanisms)are overly expensive and complex for incorporation into inexpensivedevices which may be disposable.

For many drug delivery regimes, it is desirable to provide both steadystate delivery (“basal delivery”) and instantaneous bursts of drug(“bolus delivery”) as required. In particular, in patient controlledanalgesia or PCA, it may be advantageous to provide a continuous basalinfusion of drug for chronic pain treatment, supplemented to a certainextent by bolus delivery. The bolus delivery would be activated by thepatient to deal with increased temporary pain levels (“break-throughpain”), with safeguards being incorporated to prevent overdosing.

Another area in which precisely controlled dosing can be particularlyindicated is in chronotherapeutic drug delivery, in which the drugdelivery rate varies over time. Most notably, diurnal or circadianrhythms cause variations in the amounts of certain drugs required by apatient during a 24-hour period. This is most notably required to combatvariations in disease and/or condition effects throughout a 24-hourcycle.

For example, hypertension crises, angina, and sudden cardiac death aremost likely to occur in the morning, whereas sickle cell crises andperforated ulcer crises are most likely to occur in the afternoon. Theconcept of chronotherapeutics is discussed in more detail in an articleby Smolensky & Labrecque, Pharmaceutical News 4, No. 2, 1997, pp. 10-16.The discussion in this article is principally in terms of conventionaloral dosing of drugs to take account of chronotherapeutic variations indrug uptake, effects, and requirements, but many of the principles areapplicable to other delivery routes. Circadian rhythm applications wouldalso apply to hormonal therapies.

Accordingly there is a need to provide a drug delivery device capable ofregulating drug delivery dosages to provide increased dosages at thetimes when such dosages are more likely to be required. This gives riseto a need for a device in which the delivery rate is accuratelycontrollable over a wide range of delivery rates. In general, deviceswhich are designed to deliver small amounts of drug are not particularlysuitable for high drug delivery rates without being specifically adaptedin this regard, and vice versa. Moreover there is a need to provide sucha device that is relatively compact so that it is fixed to the userduring use and disposed of when the treatment is finished. Such a devicemust be also relatively inexpensive to manufacture yet maintain accurateand reliable delivery rates

The present invention aims to provide improved drug delivery devices inwhich smaller volumes of liquid can be delivered more accurately than inprior art devices, thereby giving rise to overall more controlleddelivery rates. The invention also aims to provide such devices whichadditionally allow higher delivery rates to be provided on demand, up toand including bolus delivery. Moreover, the present invention providesfor a drug delivery device wherein the technology used to provide foraccurate delivery rates is relatively easy and inexpensive tomanufacture. Further, the present invention employs designs for the gasgenerating system and delivery system so that space within the device isminimised and parts used within the device are easy and inexpensive tomanufacture while maintaining high tolerances. In addition, the presentinvention provides for a certain amount of gas leakage while deliveringaccurate dosages. This eliminates the need for costly sealing devicesand systems which increase cost and decrease reliability in the event ofgas leakage.

SUMMARY OF THE INVENTION

The invention provides a drug delivery device having a housingcontaining a drug reservoir, and means for facilitating the expulsion ofdrug from the drug reservoir. The device also includes a mechanism incommunication with the facilitation means, that incrementally advancesand thereby drives the drug from the reservoir, and a member associatedwith the mechanism to cause the incremental advancement of the mechanismas the member moves in a first direction. The device also includes a gasgenerator located within the housing and operable to expand in achamber. The member is in transmission relation to the chamber. Inoperation, the member is driven by the movement of the chamber toadvance the mechanism and thereby drive the drug from the reservoir inincremental fashion.

Preferably, the mechanism in communication with the facilitation meanscomprises a ratchet.

Further, preferably, the member moves in a reciprocable fashion.

Further, preferably, the movement of the reciprocable member causes thestepwise advancement of the mechanism.

Further, preferably, the reciprocable member is connected to a wall ofthe chamber, whereby the reciprocation of the reciprocable member isdriven by the expansion and contraction of the chamber.

The preferred devices according to the invention take advantage of thereciprocation of a gas generation chamber to effect a stepwiseadvancement of a ratchet mechanism. Gas generation chambers which expandand contract repeatedly are advantageous over known chambers whichsimply expand over time. For example, a ratchet which has 100 teeth andis driven by a continuously expanding gas chamber will advance one stepfor every 1% increase in the chamber volume. According to basic gaslaws, a temperature rise of only 3° C. will increase the volume of a gasat room temperature by 1%. Thus, towards the end of the chamberexpansion, a temperature rise of 3° C. will drive the ratchet one stepforward independently of the gas generation rate. In contrast, a chamberwhich reciprocates will undergo a full expansion for each stepwiseadvance of the ratchet mechanism, and a 1% variation in the volume ofthis chamber will have no material effect on the fact that the chamberwill expand fully and advance the ratchet correctly.

For example, a ratchet mechanism which undergoes 100 stepwise advancesthroughout the emptying of a reservoir. If this ratchet is driven by acontinuously expanding gas chamber, a 1% increase in the volume of gastowards the end of the delivery period will advance the ratchet by an(undesired) extra step. Such a 1% expansion occurs with a temperaturechange of only 3° C. (which is approximately 1% of the room temperaturewhen expressed in kelvins). The situation is worse for devices whichrequire several hundred ratchet advances to ensure the necessarysensitivity for accurate delivery over an extended time period.

In contrast, devices according to the present invention employ areciprocating chamber which continually expands and contracts. Thisenables small-volume chambers to be employed such that the difference involume between the contracted and expanded states is orders of magnitudegreater than the change in volume arising from environmental temperaturechanges. Moreover, by employing a reciprocating chamber, less space isneeded for the chamber as the volume at maximum expansion isconsiderably less that what would be required for a continuouslyexpanding chamber at the maximum volume of expansion.

Preferably, the chamber is elastically biased to revert to a contractedstate, and wherein a venting means is provided to enable contraction ofthe chamber after gas generation has expanded the chamber.

One advantage of using a reciprocity chamber to drive a reciprocatingmechanism linked to a ratchet is that there is sufficient amplitude ofmovement in the reciprocation to advance the ratchet by the requirednumber of steps (in many cases only one step), to ensure that venting issufficiently thorough to relax the system completely, in order to arriveat a device in which the delivery rate is controlled to a high degree ofaccuracy.

For example, if the delivery volume is low (equivalent to a singlestepwise ratchet advance) every five minutes, then the gas generator canbe designed to deliver a sufficient amount of gas within one minute, andthen switch off automatically for four minutes. In the first minute, theratchet will be caused to advance by the required “tooth” (orequivalent), and then the venting means is actuated to relax the system.By the end of four minutes the system will be fully relaxed and thecycle can begin again.

This design automatically compensates for any inaccuracies in theperformance of its driving mechanism. Thus, the gas generator can bedesigned to deliver e.g. 20%±10% more than the required volume of gas(i.e. not a particularly expensive or accurate system), and still tohave an extremely accurate delivery for the following reason. If the gasgenerator generates between 10% and 30% too much gas on each cycle, theratchet will advance by a single “tooth”, but it is equally certain thatit will not be pushed to advance by a second tooth. Thus, when the gasgeneration ceases, a certain amount of controlled overpressure or stresswill be present in the system, but the amount of drug delivered will beprecisely known. Then when the gas is vented, the overpressure isreleased and the system returns to equilibrium. Thus, the accuracy ofdelivery at the end of the five minute cycle is independent of whetherthe generator generated 10% or 30% too much gas.

It should be noted that the accuracy of the system is controlled by thetolerances of the ratchet mechanism, the timer, the reciprocity chamber,the venting system and the gas generator.

In some embodiments, the venting means is passive and allows escape ofgas therethrough when the chamber is pressurised relative to atmosphericpressure. In other embodiments, there is designed to be venting meanswithin the gas generator. Such venting means may connect sub-chamberswithin the gas generating means. The venting means enables thesub-chambers to increase and decrease pressure therein more efficiently.

In some embodiments, the gas generator is adapted to generate gas at arate higher than the venting rate. When the gas generator is active, thechamber becomes pressurised and expands, and when the gas generator isinactive, the venting means causes depressurisation and contraction ofthe chamber. Minor leaks in the system, provided that they are not soserious as to prevent the chamber from fully pressurising, do not haveany significant effect on the operation or accuracy of the device. Thisenables a gas generating system to deliver extremely small volumes ofdrug in a highly controlled, accurate manner, without employing anyelaborate gas generation system, or any special leakproofing of the gaschamber. Also, the gas generation rate should exceed the venting rate sothat the error of movement of the reciprocator member errs to the sideof excessive pressure rather than too little pressure. If there isinsufficient pressure (i.e. caused by the leakage rate exceeding thepressurisation rate, the force needed to move the reciprocating memberwill be insufficient and the pawl on the ratchet will not move. Thus,the volume of drug will not be advanced through the cartridge anddelivered to the user.

In alternative embodiments, the gas pressure of the gas generator isdivided between at least two cells. A first cell has a more permeablemember and is designed for minimum gas leakage. The first cell also hasa controllable vent associated therewith. The vent allows excess gas toescape from the first cell but prevents the escape of gas at a stage inthe cycle when the member of the first cell is needed to deflect so asto cause forward movement of the ratchet. The alternative embodiment isalso designed so that the latter part of the cycle allows the re-openingof the first cell vent to enable gas therein to quickly escape and causethe member to return to its initial resting position.

In some preferred embodiments, the venting means comprises a permeableor semi-permeable member. Currently one of the most preferred member isa silicone membrane. In another embodiment, there are at least twomembers with varying permeability. The less permeable material ispreferably bromo-butyl, ethylene propylene or EPDM, and the morepermeable member is preferably silicone rubber.

Suitably, the mechanism is caused to advance as the chamber undergoesexpansion. Alternatively, the mechanism may be caused to advance as thechamber undergoes contraction. While it is possible to employ amechanism which drives the ratchet forward during both expansion andcontraction strokes, it is preferred to employ a single driving stroke(either contraction or expansion) during a reciprocation cycle for lowerdelivery rates.

Suitably, the member comprises a lever extending between the chamber andthe mechanism.

The use of a lever mechanism enables the amplitude of movement of theexpanding chamber to be accurately converted to the correct amplitude ofmovement to drive the ratchet.

In certain preferred embodiments, the mechanism comprises a rigidratchet element having spaced formations on a surface thereof.

Preferably, the formations have a sawtooth cross section, although theformations may be in the form of grooves on a surface of the rigidratchet element.

Preferably, the mechanism includes a pawl carried on the member, thepawl being adapted to make ratcheting engagement with the formations onthe rigid ratchet element.

Further, preferably, the pawl is resiliently biased against theformations on the rigid ratchet element.

Suitably, the pawl is in the form of a substantially flat spring an endof which bears against the formations on the rigid ratchet element.

Such a pawl is adapted to allow the ratchet element to slide with littleresistance in one direction but to prevent any movement in the oppositedirection.

In preferred embodiments, the formations are regularly spaced along therigid ratchet element, and the pawl comprises a pair of pawl membersresiliently biased against the rigid ratchet element at different pointsalong the length of the rigid ratchet element, the axial distancebetween the pair of pawl members being different to the axial distancebetween successive formations.

The advantage of this arrangement is that by locating the ratchetinglinkage between the pawl and the ratchet teeth, the teeth makealternating contact with either pawl member. The ratcheting memberadvances by increments which are less than the actual difference betweensuccessive formations on the ratchet.

In particularly preferred embodiments, the distance between successiveformations is twice the distance between the pawl members. This meansthat then the ratchet advances in half steps and enables accuratedelivery of even smaller incremental volumes of drug (if a full step iscounted as equating to the distance between successive ratchet teethformations.)

The definitions of “half steps” and “full steps” is not as arbitrary asit may appear, since one of the main constraints on the accuracy ofdelivery of small volumes, as explained above, is the manufacturingtolerances of the ratcheting teeth.

It is envisaged that one of the least expensive ratcheting mechanisms,and therefore one of the most suitable for large scale production, is astamped plastics ratchet bar having a sawtooth surface, against which apawl in the form of a leaf spring may be biased. The main limitation onaccuracy in this system is likely to arise from the spacing of adjacentsawtooth formations which may not be able to be made accurately with therequired spacing. In such cases the minimum delivery volume, all otherthings being equal, will be limited by this component. However, byemploying a specially designed pawl or leaf spring (which can be made tomuch higher tolerances from metal materials at relatively low cost),accuracy is doubled, and the minimum deliverable volume may be halved.

In alternative embodiments, the ratchet teeth are regularly spaced alongthe rigid ratchet element, and the pawl comprises three or more membersresiliently biased against the rigid ratchet element at regularintervals along its length. The axial distance between each successivepair of pawl members is chosen to be different to the axial distancebetween successive ratchet teeth.

Suitably, in such cases, the distance between successive ratchet teethis given by the number of pawl members multiplied by the distancebetween each successive pair of pawl members.

Thus, by analogy with the two pawl members spaced at half of thedistance between successive ratchet teeth, three or four pawl memberswould preferably be spaced at intervals of a third and a quarter,respectively, of the distance between successive ratchet teeth on theratchet element.

Suitably, the pawl is in the form of a resilient member which terminatesin a plurality of fingers biased against the ratchet element.

A preferred embodiment in this regard is a pawl which comprises a flatspring which is partly split to define fingers of different lengths.

In another preferred embodiment, the ratchet element comprises a helicalspring and the pawl comprises one or more fingers which engage with thecoils of the spring. The coils of a helical spring easily engage withthe pawl fingers, and the regular spacing of the coils of a helicalspring enable it to be used as a ratchet element.

A further advantage of this embodiment is that the size of the devicecan be minimised by taking advantage of the flexibility of the spring.Thus, whereas a rigid ratchet bar protruding from a drug cartridgebefore use might provide an unacceptably long device for certainapplications (after use, the ratchet element might be partly or totallyaccommodated within the empty cartridge interior), a helical spring canbe bent to be parallel with the cartridge to reduce the overall length.

Preferably, in embodiments which employ a helical spring in lieu of aratchet element, one or more fixed fingers are mounted in fixed positionrelative to the housing, and one or more reciprocable fingers aremounted on the mechanism, such that when the one or more reciprocablefingers move in a first direction they engage the coils of the helicalspring to drive the helical spring in the first direction, and when theone or more reciprocable fingers move in an opposite direction, the oneor more fixed fingers engage with and hold the coils of the helicalspring preventing it being driven back in the second direction, wherebythe fixed and reciprocable fingers co-operate to drive the helicalspring in one direction only.

The operation of this embodiment will become clearer from thedescription below. The fingers are generally arranged such that thehelical spring is forced to alternately slip past the fixed fingers andthe reciprocable fingers, which gives rise to a uni-directional drivingmovement. Suitably, each finger is inclined in the first direction. Thismakes it easier for the helical spring coils to slip past the fingers inthis direction, and more difficult for the coils to push back in theopposite direction against the fingers.

Preferably, the position of the one or more fixed fingers relative tothe one or more reciprocable fingers is such that the helical spring isdriven by the reciprocable fingers towards the fixed fingers.

This feature helps prevent a situation which may develop in which aflexible helical spring is pulled by the reciprocable fingers away fromthe fixed fingers, but rather than slipping past the fixed fingers, thehelical spring merely stretches, such that when the reciprocatingfingers move back towards the fixed fingers the helical spring simplyrelaxes, without any net movement having taken place. The solution tothis problem is achieved in part by pushing the helical spring towardsthe fixed fingers as the driving step of the delivery action.

Suitably, the minimum distance between the fixed and reciprocablefingers, respectively, is not greater than ten times the distancebetween adjacent coils of the helical spring when the helical spring isin a relaxed position. Preferably, this minimum distance between thefixed and reciprocable fingers, respectively, is not greater than fivetimes the distance between adjacent coils of the helical spring when thehelical spring is in a relaxed position, most preferably not greaterthan twice the distance between adjacent coils.

The reason for this again relates to the problem of using a flexiblespring which is likely to stretch rather than be displaced. While theproblem could be overcome by using a sufficiently stiff spring, thiswould defeat the purpose of using this type of spring, which is to allowthe ratchet element to be bent within the housing to reduce overalldimensions. While even a stiff spring can be bent under sufficientforce, this tends to generate frictional forces which would prevent thespring from sliding past the ratchet fingers.

Instead, setting the two sets of fingers close together allows even arelatively very flexible spring to be used without much stretching,since for a given overall amount of stretching, a greater stiffness isachieved by concentrating this stretching over just a few coils.

Thus, in certain preferred embodiments, the minimum distance between thefixed and reciprocable fingers, respectively, is approximately equal tothe distance between adjacent coils of the helical spring when thehelical spring is in a relaxed position.

Suitably, the mechanism comprises a flexible ratchet element which issufficiently stiff to drive medicament from the chamber when driven bythe member, and sufficiently flexible to be bent before it meets themember, whereby the overall length of the device is reduced relative toa device in which a rigid ratchet element protrudes linearly from themechanism before use. Thus, the flexible member may be, for example, apiece of bendable thermoplastics stamped or molded with a ratchetsawtooth profile.

In order for this embodiment to be useful, the flexible member shouldhave a degree of flexibility which allows it to be bent sufficiently toreduce the overall dimensions of the device. Furthermore, it mustnevertheless be sufficiently stiff to transmit the driving force of theratcheting mechanism without buckling or distorting to any great extent.This can be achieved by restraining the degree of freedom of movement ofthe member.

For example, by driving a flexible member into a conduit in which theflexible member makes a good fit, the flexible member is prevented bythe conduit walls from bowing or buckling sideways. Thus, when driven bythe ratchet mechanism the flexible member is constrained to transmit thedriving force to the piston, and despite its flexibility it acts as adrivable piston rod. Other mechanisms not requiring a restrainingconduit are also possible, as described below.

Preferably, the mechanism comprises two or more co-operating flexibleratchet elements which are individually sufficiently flexible to be bentbefore they meet the member but when joined together are togethersufficiently stiff to drive medicament from the chamber when driven bythe member.

Further, in a preferable embodiment, the two or more co-operatingflexible ratchet elements are bent away from one another before theymeet the member.

Suitably, the device according to the invention further compriseselectronic control means for controlling the delivery rate. Preferably,the electronic control means comprises a timing mechanism whichalternately energises and de-energises the gas generating mechanism forcontrolled periods.

As explained above, by choosing an energized period long enough toalways guarantee complete advancement of the ratchet mechanism by apredetermined number of steps, and by providing a de-energised period(e.g. for venting) which allows relaxation of the system, the amount ofdrug delivered in this overall cycle is accurately controllableindependently of variations (within reason) in the gas generation rate.

Furthermore, the use of a timer allows the overall cycle length to bevaried in a controlled manner over time, thereby providing an accuratelycontrollable device which delivers at a time-varying rate. Such devicesfind a particular application in the field of chronotherapeutics.

Further, preferably, the electronic control means is programmable fordifferent delivery programs. The control means may be user-programmableor a single unit may be factory-programmable for different deliveryregimes (e.g. for different drugs. Preferably, the device according tothe invention further comprises means for manually adjusting thedelivery rate. This allows for a certain degree of flexibility whichmight be desirable where the user can safely have an amount of controlover the treatment. Alternatively, it can be set by the physician orpharmacist and disabled to prevent patient interference.

In preferred embodiments, the member reciprocates to cause theincremental advancement of the mechanism and the means for manuallyadjusting the delivery rate comprises means for limiting the travel ofthe member, whereby the volume of drug delivered on each reciprocatingstroke is controllable. Thus, a simple advancing screw can control astop against which any reciprocating element ends its travel. If this isused, adjustment of the screw will provide a control mechanism. Forexample, a device could be designed with three delivery rates, namelylow, medium and high, corresponding respectively to one, two and threeratchet advancements per reciprocation. A simple mechanism woulddetermine how far the reciprocating mechanism is allowed to advance oneach stroke, to determine the delivery rate. Clearly, more sophisticatedembodiments could also be achieved. Devices having the ability todeliver bolus doses of drug are preferred in therapies such as patientcontrolled analgesia.

In a preferred embodiment, the means for manually adjusting the deliveryrate provides the user with the ability to deliver a bolus dose of drug.It is advantageous if the bolus dose can be delivered without thisinterfering with the normal basal delivery rate.

When the reciprocating mechanism comprises a lever arrangement, it ispreferred that the means for manually advancing the mechanism comprisesmeans for manually advancing the lever extending between the chamber andthe mechanism, operable from the exterior of the housing. Any suitablemechanism, such as a knob, button or lever can be used to operate thelever.

Preferably, the mechanism comprises a ratchet and wherein the means formanually advancing the mechanism comprises a pawl which is manuallyreciprocable from the exterior of the housing.

Further, preferably, the mechanism for manually advancing said lever isprovided with gradations corresponding to a number of stepwise advancesof the ratchet mechanism.

For example, in delivering insulin, the advancing means could be markedin units which would be understood by the patient, and the scale wouldbe calibrated to correspond to the delivery of the correct dose.

In a further aspect, the present invention provides a method ofdelivering drug to a patient. The method includes affixing a drugdelivery device to the surface of the patient's skin. The drug deliverydevice having a housing containing a drug reservoir, means forfacilitating expulsion of drug from the drug reservoir, a mechanism incommunication with the facilitation means, operable to undergoincremental advancement and thereby drive the drug from the reservoir, amember operatively associated with the mechanism to cause theincremental advancement of the mechanism as the member moves in a firstdirection, and a gas generator located within the housing and operableto expand in a chamber, the member being in transmission relation to thechamber. The method further includes activating the device whereby themember is driven by the movement of the chamber to advance the mechanismand thereby drive the drug from the reservoir in incremental fashion.

Other objects, features and advantages of the present invention willbecome apparent upon reading the following detailed description, whentaken in conjunction with the drawings and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be now be described with reference to theaccompanying drawings, which illustrate the preferred embodiments of thepresent invention and in which:

FIG. 1 is a sectional plan view of a first embodiment of a drug deliverydevice according to the invention;

FIGS. 2-5 are schematic views of a detail of the embodiment of FIG. 1shown at successive points in the operating cycle;

FIG. 6 is a sectional plan view of the embodiment of FIG. 1, in use;

FIGS. 7-11 are sectional side views of a second embodiment of a deviceaccording to the invention, shown at successive points during its use;

FIG. 12 is a simplified sectional plan view of a third embodiment of adrug delivery device according to the invention;

FIG. 13 is a cross sectional side view of the embodiment of FIG. 12,taken along the line XIII-XIII;

FIG. 14 is a sectional plan view of a fourth embodiment of a drugdelivery device according to the invention;

FIG. 15 is a cross sectional side view of the embodiment of FIG. 12,taken along the line XV-XV;

FIG. 16 is a graph showing the test results of an 80 hour test whichplots delivery pressure and amount of drug delivered against time;

FIG. 17 is an enlarged detail of a portion of the graph of FIG. 16;

FIG. 18 is a sectional plan view of a fifth embodiment of a drugdelivery device according to the invention;

FIG. 19 is a sectional side view of the embodiment of FIG. 18;

FIG. 20 is a sectional plan view of the embodiment of FIG. 18, as it isbeing prepared for use;

FIG. 21 is a sectional side view of the embodiment of FIG. 18 when readyfor use;

FIG. 22 is a sectional plan view of a sixth embodiment of the drugdelivery device according to the invention;

FIG. 23 is a sectional plan view of the embodiment of FIG. 22 when readyfor use;

FIG. 24 is a cross-sectional view along line A-A of the embodiment ofFIG. 22;

FIG. 25 is a cross-sectional view along line B-B of the embodiment ofFIG. 22; and

FIG. 26 is a schematic drawing representing the various parts of the gasgeneration sub-assembly of the embodiment of FIG. 22.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring now in more detail to the drawings, in which like numeralsindicate like parts throughout the several views, in FIG. 1 there isindicated, generally at 10, a drug delivery device according to theinvention. The device 10 comprises a housing 11 containing a cartridge12 filled with a drug 13. The cartridge 12 is provided with a needle 14extending from a first end 15 of the cartridge for delivery of drug 13to a patient. A piston 16 is slidably received in the cartridge 12, suchthat when the piston 16 is pushed towards the first end 15, drug isforced from the cartridge 12 out through the needle 14.

The piston 16 is mounted on a ratchet bar 17 which is driven by a pawl18 mounted on a reciprocable lever 19. Lever 19 is mounted on an axis 20at one side 21 and is connected to a driving rod 22 at the other side23, whereby reciprocation of the driving rod 22 causes pawl 18 toreciprocate with respect to the ratchet bar 17. As will be explained ingreater detail below, this causes the ratchet bar 17 to advance stepwisetowards the first end 15 of cartridge 12 and thereby drive the drug 13from the cartridge.

The driving rod 22 is in connection with a flexible diaphragm 24 whichdefines a wall of a gas generation chamber 25. A battery 26 is connectedvia a microprocessor 27 to an electrolytic cell 28 which is operable togenerate a gas into chamber 25. When gas is generated, the chamberexpands and causes the diaphragm 24 to move. This movement pushes thedriving rod 22 in the direction away from the first end 15 of cartridge12. The movement is opposed by a return spring 29 which biases the lever19 towards the first end 15. After a certain period of time the chamber25 is fully expanded and the supply of current from the battery 26 tothe electrolytic cell 28 is switched off by the microprocessor 27.

A silicone membrane 30 defines a wall of the chamber 25. The membrane 30is slightly permeable and thus allows a controlled leakage of gas fromthe chamber 25. When the chamber 25 is in its expanded state, the forceof return spring 29 will act to decompress the chamber 25 by gas leakingthrough membrane 30. After the chamber 25 has fully decompressed in thismanner, the lever 19 and hence the pawl 18 will have made one completereciprocation thereby advancing the ratchet bar 17 by a fixed step.

For example, the cycle might be chosen to allow the delivery of aquantity of drug corresponding to the advancement of a single step ofthe ratchet bar 17 every five minutes. In such a case the electrolyticcell 28 could be switched on for one minute and then switched off forfour minutes. As long as the timing of the microprocessor is accurate,this will ensure that precisely one stepwise advance is made in thatfive minute period.

The precision of device 10 is to a certain extent independent of theexact quantity of gas generated because the ratchet bar 17 is quantised,i.e. it can only move by a fixed step (or number of steps) at a time.Similarly, because the membrane 30 provides a controlled constantleakage from the system even during gas generation, other minor leakswhich might affect the accuracy of conventional gas driven deliverydevices are not important (although of course if the leak is bad enoughthe chamber will be unable to pressurise fully when the gas isgenerating).

It will be noted from the first embodiment shown in FIG. 1 that pawl 18is split in two halves, i.e. a longer half 31, and a shorter half 32.The pawl 18 is a leaf spring which is biased down onto ratchet bar 17.The halves 31,32 of the pawl 18 are of unequal length.

FIG. 2 shows a cross-sectional enlarged view of a portion of the ratchetbar 17 which has a series of evenly spaced steps or teeth 33,34. Thedifference in length between the halves 31,32 of the pawl 18 is exactlyhalf of the distance between adjacent teeth 33,34 on the ratchet bar 17.It can be seen that each tooth 33,34 has a sloped surface 35 having apeak 36 and a trough 37, as shown in detail in FIG. 2A. At the point ofthe cycle illustrated in FIG. 2, the longer half 31 of the pawl 18presses against the sloped surface 35 of tooth 33, midway between thepeak 36 and trough 37, and the shorter half 32 presses against thetrough 37 of the adjacent tooth 34.

When gas is generated to drive the driving rod 22 in the direction awayfrom the first end 15 of cartridge 12 (see FIG. 1), the two halves 31,32of the pawl extending from lever 19 (FIG. 1) move left as viewed in FIG.2. This results in the situation shown in FIG. 3, in which the shorterhalf 32 has been pushed back up the sloped surface 35 of tooth 34, andthe longer half 31 has passed the peak 36 of tooth 33 to rest in thetrough 37 of adjacent tooth 34 formerly occupied by the shorter pawlhalf 32. In practice, the distance travelled by the pawl 18 will beslightly further than the minimum necessary so as to allow for anyvariations between components. This does not affect the operation of theinvention as a whole since the pawl 18 when making its return strokewill press against the correct tooth as it begins its travel.

After the gas generation chamber 25 is pressurised fully and the device10 is in the FIG. 3 position, gas generation ceases and the controlledleakage from the chamber 25 allows the return spring 29 to push thelever 19 back to its starting position, leading to the configurationshown in FIG. 4.

In FIG. 4, the longer pawl half 31 when being driven forward (i.e. tothe right) has abutted against tooth 33 and pushed the ratchet bar 17forward. This completes one reciprocation of the pawl 18, and when theelectrolytic cell 26 again fills the gas generation chamber 25 to drivethe pawl 18 to the left (as seen in FIG. 5), the short pawl half 32passes over the peak 36 of tooth 34 as shown in FIG. 5, ready to pushagainst tooth 34 and thereby once again advance the ratchet bar 17.

The reason for using a pawl in two halves of unequal length is seen byobserving the movement of a point 38 on the ratchet bar. After acomplete cycle has been completed, i.e. from FIG. 2 to FIG. 5, the point38 has moved by a distance ½ L. This is exactly half of the length L ofone of the teeth 33,34 on the ratchet bar 17, as can be seen withreference to FIG. 2A.

In effect this means that although the manufacturing quality andtolerances are such that the tooth length is not as small as what wouldbe desired (perhaps because the manufacturing technique, chosen for itscost effectiveness, is incapable of achieving a smaller length ofadjacent teeth), it is nevertheless possible to deliver amounts of drugcorresponding to an advance of half of the length of one of the teeth33,34, thereby halving the minimum deliverable volume.

FIG. 6 shows the device of FIG. 1 in operation at the completion of gasgeneration, and before the lever 19 has begun its return stroke. Thus,it can be seen that gas generation chamber 25 has expanded by pushingthe diaphragm 24 outwards, and the lever 19 is thus pivoted on its axis20 against the force of the return spring 29. When the lever 19 isdriven back to the FIG. 1 position, a small volume of liquid drug 13will be forced from the cartridge 12.

Because the device of FIG. 1 delivers small volumes in a stepwisefashion, it is possible to achieve an extremely low delivery rate. Forexample instead of operating in 5-minute cycles, the gas generator 25could be activated for 1 minute as previously described and thenswitched off for 59 minutes to give cycles of one hour duration. Unlikeother gas-driven devices which cannot achieve these long-term low-volumerates because of pressure losses in the system, the device 10 of thepresent invention does not require a system pressure to be maintainedabove atmospheric pressure.

As can be seen from FIGS. 1 and 6, the volume of the gas generationchamber 25 is small relative to the size of the device. This minimisesvariations in the volume of gas per stroke, and helps ensure a constantdelivery rate. Preferably, the device 10 will generate in excess of10-30% volume of gas over the required amount on each stroke so that thedevice can compensate of variations due to temperature, atmosphericpressure, materials used, etc. (The device will never drive the ratchet10-30% further than necessary, since the ratchet can only move in fixedsteps.) This extra gas is stored as an overpressure in the system and isof course released during the venting part of the cycle.

FIG. 7 shows a cross-sectional side view of a second alternativeembodiment of the present invention, indicated generally at 50. Thedevice 50 is similar in most respects to the first embodiment shown inFIG. 1. In the device of FIG. 7, however, the pawl 51 is not split intotwo halves, so that it advances the ratchet bar 52 by full steps equalto the tooth length (“L”). In all other respects the device 50 isidentical to the device 10 of FIG. 1. It can be seen from FIG. 7 thatthe needle 53 of the device 50 (as with the FIG. 1 device) is bent at90° to the axis of the cartridge 54.

The device 50 of FIG. 7 is shown before use. A protective sheath 55 isprovided on the needle 53 and a displaceable lower cover 56 is hinged tothe main housing 57 by a hinge (not shown). The displaceable lower cover56 and the main housing 57 are prevented from moving relative to oneanother by a safety tab 58. The lower surface 61 of the displaceablecover 56 is covered by a contact adhesive which is protected beforeapplication to the user by a protective liner 60. The liner 60 has apull tab 59 to ease removal of the liner by the user immediately beforeapplication of the device 50.

Before use, the protective sheath 55 is removed as indicated in FIG. 8by grasping and pulling the pull tab 59. This also causes the releaseliner 60 to be pulled away revealing the contact adhesive on the lowersurface 61 of the displaceable cover 56. The lower surface 61 is adheredto the user's skin. Then, the safety tab 58 is pulled away from thedevice 50 as shown in FIG. 9.

As shown in FIG. 10, the main housing 57 is then pressed towards theskin whereupon it snaps towards the displaceable cover 56. The needle 53projects beyond the lower surface 61 to penetrate into the skin forsubcutaneous drug delivery.

The delivery mechanism is then actuated, either by the user, or morepreferably, in automatic fashion by the microprocessor. Upon activationeither manually or automatically, the ratchet bar 52 is advanced by thepawl 53 in stepwise manner as described above with regard to theoperation of the first embodiment as shown in FIG. 1.

When delivery is completed (see FIG. 11) the user can see the piston 62through an aperture 63 in the main housing 57 as shown in FIG. 11. Themain housing 57 is then pulled away from the skin whereupon it snapsaway from the displaceable cover 56 and locks in this position by alocking mechanism (described in more detail in our U.S. ProvisionalApplication No. 60/045,745) which prevents further actuation of thedevice, i.e. prevents the needle 53 from projecting beyond thedisplaceable cover 56 due to further relative movement of the mainhousing 57 and the displaceable cover 56.

In FIG. 12 there is indicated, generally at 70, a further embodiment ofa device according to the invention. In the illustration of thisembodiment, only those details necessary to understand the differencesrelative to the devices of the first and second embodiments are shown,and thus the gas generation mechanism, for example is not shown.

In the device of FIG. 12, the ratchet bar has been replaced by a helicalspring 71. A lever 72 is caused to reciprocate in identical manner tothat previously described. A pair of resilient reciprocable fingers 73are mounted on the lever 72 and reciprocate as the lever reciprocates.These reciprocable fingers 73 are inclined in the direction of movementof the piston 74 as it empties the cartridge 75. Thus, when they move inthe direction in which they are inclined they tend to grip and push thecoils of the helical spring 71 forward. As the helical spring 71 movesforward it slips past a pair of resilient fixed fingers 76 mounteddirectly in front of the reciprocable fingers 73, and inclined inidentical manner.

When the lever 72 moves away from the piston 74 (as the gas generatorgenerates the gas) the helical spring 71 is prevented from moving backbecause it is gripped by the fixed fingers 76. The reciprocable fingers73 thus slip over the coils of the helical spring 71. When the lever 72reverses its travel again the helical spring 71 is again gripped andpushed forward by the reciprocable fingers 73.

FIG. 13 shows a sectional side view of the device taken along the lineXIII-XIII (in FIG. 12), in which the fixed fingers 76 and helical spring71 are visible.

Thus, the arrangement of reciprocable fingers 73 and fixed fingers 76act as a pawl and the helical spring 71 acts as a ratchet, such that oneach reciprocation of the lever 72, the helical spring 71 advances by anamount equal to a set number of coil diameters. Accordingly, as withpreviously described embodiments, precisely controlled delivery ratesare achievable, and in particular, extremely low volume delivery ratesare possible with this invention.

While there is a tendency for the helical spring 71 simply to stretchbetween the reciprocable fingers 73 and the fixed fingers 76, thistendency can be overcome by choosing the correct stiffness (for bothsets of fingers). Furthermore, the closer together the reciprocablefingers 73 and fingers 74 are mounted, the less likely the helicalspring 71 is to stretch, since the force is spread over fewer coils.

One advantage of this embodiment is that because the helical spring 71is curved within the device 70, it does not have to project directly outof the cartridge 75 and thus a shorter device can be realised, or theshape of the device can be varied as required.

A further embodiment of the present invention is shown incross-sectional plan view in FIG. 14. The device, indicated generally at80, is in many respects identical to the device of FIG. 1 but differs inthat as well as the gas-driven lever 81, a second manual lever 82 isprovided. Manual lever 82 is mounted on a common axis 83 with gas-drivenlever 81, as can be seen referring additionally to FIG. 15. Manual lever82 passes under the ratchet bar 84 and also carries a second pawl 85.Both the upper surface 86 and lower surface 87 of ratchet bar 84 areprovided with ratchet teeth, so that either gas-driven lever 81 ormanual lever 82 can drive the ratchet bar 84 forward.

Thus, in normal operation, gas-driven lever 81 will drive the drug fromthe cartridge 88, and in this mode, the ratchet bar 84 simply slidespast the pawl member 85 on manual lever 82 as described previously.However, if a bolus dosage of drug is required at any point in time, themanual lever 82 can be actuated to advance the ratchet bar 84 by apre-determined number of teeth. Referring to FIG. 14, the manual lever82 can be seen to have an adjustable threaded locking member 89 whichdetermines the extent of travel of the manual lever 82, and hence thevolume of the bolus delivery. In FIG. 14, the lever 82 is prevented fromtravelling because the threaded member 89 is fully torqued, and thislocks the lever 82 preventing it from being actuated. However, if thethreaded member 89 is partially torqued and thereby partially withdrawnfrom the housing in the axial direction, the lever 82 is free to moveinwards by an amount equal to the distance of axial travel of thethreaded member 89. The lever 82 can then be actuated by depressing thethreaded member 89. The degree of travel of the lever 82 is determinedby the extent to which the threaded member 89 is turned, and byproviding marked gradations on the threaded member 89 one can give theuser visual control over the volume delivered in such a bolus dosage.

The movement of the ratchet bar 84 under the action of the second pawl85 is independent of the primary pawl-and ratchet mechanism. Thus, thesecond pawl 85 will, when actuated manually, advance the ratchet bar 84by a whole number of steps. When advanced in this way, the ratchet bar84 slides under the pawl member 90 on gas-driven lever 81, but this hasno effect on the basal delivery rate or on the operation of thegas-driven delivery mechanism 80. Thus, each individual ratchetmechanism is independent of the other, and bolus delivery can take placeagainst the background basal rate without complication.

FIG. 16 is a graph of typical results achieved in a test of a deviceaccording to the invention, of the design shown in FIG. 1. The graphshows two lines, namely the cumulative delivery of drug against time(the stepwise steadily ascending line), and the delivery pressureagainst time (the line consisting of a succession of sharp peaks andtroughs).

It can be seen that the device was tested over an 80 hour period (morethan 3 days) and delivered just under 1.35 grams of drug solution inthis time. This gives a delivery rate of less than 17 μg/hour.Furthermore, this delivery rate is absolutely constant, i.e. shows nodeviation from a straight line. Accordingly, the device of FIG. 1 has adelivery rate whose accuracy is unmatched in the prior art, particularlyfor extremely slow delivery rates.

FIG. 17 shows a portion of the graph of FIG. 16 in greater detail, overa five hour period in the middle of the test. It can be seen that thepressure on each cycle immediately shoots up to a maximum, and thenslowly falls off as gas is released through the silicone membrane.

It can be seen that the delivery overpressure reaches over 400 mbar (0.4atm or 40 kPa) on each cycle, and this assists in providing a constantdelivery rate, since any minor needle blockages will be forced out, andvariations in blood pressure (when intravenous delivery is effected willhave a negligible effect on the delivery rate. This is to be contrastedwith other low volume pumps which generally achieve low delivery rateswith low delivery pressures.

A further alternative embodiment is illustrated in FIG. 18. The device,indicated generally at 100, has a housing 101 containing an internalneedle 102 connected via a length of flexible tubing 103 to a deliveryneedle 104 (seen in sectional side view in FIG. 19). As with previouslyillustrated embodiments, delivery needle 104 is protected by a sheath105 before use. Internal needle 102 is also protected by a sheath 106which is provided with a tab 107 extending the length of an internalbore 108 to the exterior of the housing 101.

Flexible tubing 103 is carried on a ratchet bar 109 which can be drivento move the internal needle 102 in the direction of the internal bore108. It can be seen from FIG. 19 that a leaf spring 110 acting as a pawlis carried on a lever 111 to drive the ratchet bar in the mannerpreviously described. Referring back to FIG. 18, the lever 11 is drivenby the expansion and contraction of an electrolytic cell 112 which ispowered by batteries 113.

FIG. 20 shows a step in the preparation of device 100 for use. Theinternal sheath 106 has been removed and is no longer visible, therebyexposing internal needle which is in the centre of a cylindrical cup114. A drug cartridge 115 is provided in the form of a cylindricalcontainer 116 sealed at its open end 117 by a piston 118 slidablyreceived in the container 116. Bore 108 is dimensioned to receivecartridge 115, and a pair of resilient projections 119 inside the bore108 hold the cartridge in place when it is pushed home within the bore.

FIG. 21 shows the device 100 when the cartridge 115 has been pushedhome. Internal needle 102 penetrates piston 118, such that the internalneedle 102 is in fluid communication with the drug inside the cartridge115. Thus, movement of the ratchet bar 109 into the cartridge 115 causesthe piston 118 to be pushed along the length of the cartridge 115, andthereby pump drug through the internal needle 102 and flexible tubing103 to the delivery needle 104. As the internal needle 102 moves withthe piston into the cartridge 115, the flexible tubing 103 is pulledbehind, thereby maintaining communication between internal needle 102and delivery needle 104.

Another advantage of flexible tubing 103 is that it enables deliveryneedle 104 to be mounted at any point on the device, and thus theplacement of the delivery needle in this embodiment is not constrainedby the design of the other features.

Although the electrolytic cell 112 in device 100 operates in exactly thesame manner as the cells in previously described embodiments, theconfiguration of lever 111 and the pivot 119 on which it is mountedcauses pawl 110 to advance ratchet bar 109 during the gas generationstep rather than during the venting step.

A further embodiment is shown in FIGS. 22-26. In FIG. 22, the embodiment120 comprises a housing 121 containing a cartridge 122 filled with adrug 123. The cartridge 122 is provided with a needle 124 for deliveryof drug 123 to a patient. The cartridge 122 includes a piston 125 whichis slidably received in the cartridge 122. The piston has an outerrecess 126 for receiving a needle sterility cover 127. The needlesterility cover 127 covers a first end 128 of the needle 124 andprevents contamination thereto. A second end 129 of the needle 124 isconnected to a length of tubing 130. The tubing 130 has a first end 131and a second end 132, as shown in FIG. 24. The tubing 130 second end 132is secured within an activation assembly 163. A second needle 134 isalso secured to the activation assembly 163. A drug pathway 133 ismachined into the activation assembly 163, and the tubing 130 and secondneedle are secured within the activation assembly by means of anadhesive, preferably an ultra-violet bonding agent. A second needlesterility cover 135 is slidably received on the exterior end 136 of thesecond needle 134. Prior to use, the second needle sterility cover 135is manually removed so as to uncover the exterior end 136 of the secondneedle 134 so that it is ready for penetration into the user's skin.

Returning now to FIG. 22, the piston 125 and needle 124 are mounted on aratchet bar 137 having a multitude of stepped increments 138 thereon.The ratchet bar 137 is moved by a leaf spring 139 integral with areciprocating lever 140. The lever 140 is mounted on an axis 141 and hasa return spring 142 that applies constant pressure to the lever 139 in asingle direction. The lever 139 rests against a gas generatorsub-assembly 144 and moves in response to pressure differentiationcreated therein.

The gas generation sub-assembly 144, includes a pair of electrolyticcells 145, 146, as shown in FIG. 26. The first cell 145 is thepropulsion cell. The propulsion cell 145 has a first diaphragm 147 madeof a low permeability material, such as bromo-butyl, ethylene propylene,or EPDM. The lever 140 rests against the first diaphragm 147. The secondcell 146 has a second diaphragm 148 thereon. The second diaphragm 148 ismade of a high permeability material, such as silicone rubber. The firstcell 145 has a hose 149 extending from the side of the first cell 145 toabove the surface of the top of the second cell 146. A gap 143 iscreated between the end of the hose 149 and the top surface of thesecond cell 146. The cells 145, 146 are activated with electrical energyfrom batteries 150.

Additional components in the present embodiment 120 include a drugcartridge recess 151, as shown in FIG. 23. The drug cartridge has asleeve 152 for receiving and supporting the cartridge 122 and ensuringsafe and accurate operation of the device 120. The sleeve 152 isslidably received into the recess 151. The sleeve 152 has a lip 153 onthe exterior at the insertion end 154 of the sleeve. The recess 151 hasa shelf 155 for receiving the lip 153 of the sleeve when the cartridge122 is fully inserted, as shown in FIG. 21. A cartridge receivingchannel 156 is located within the housing 121 and is proximate to therecess 151. The channel provides further support for the cartridge whenit is inserted within the device 120. The channel includes an outer edge157, an inner edge 158 and an arched portion 159. The outer and inneredges are parallel and align with the cartridge recess to guide andsupport the cartridge 122 upon insertion and during use. The archedportion 159 of the channel is integral with the inner edge 158 and iscurved away from the cartridge and ratchet assembly. Prior to operation,the arched portion 159 rests against a depressable button 160 that ispart of the gas generating sub-assembly 137. The button 160 has apuncturing device on the inner surface thereof. When depressed, thepuncturing mechanism breaks a seal 161 of the compartment 162 containingthe chemical entity used in the electrolytic cells 145, 146 of the gasgenerating sub-assembly 144, as shown in FIG. 22. The chemical entity istypically potassium chloride, and in the present embodiment, it ispreferably in a less viscous form so as to enable the liquid to move togaseous form more quickly.

With this design, in the event the electrical connection is made priorto use, gas generation in the sub-assembly 144 is not possible becausethe gas generating chemical is sealed within its compartment 162. Inaddition, this design prevents operation of the device unless the drugcartridge is fully engaged. The arched portion 159 is located so as toonly be deflectable by the drug cartridge when the cartridge is in itsfully inserted position. Thus, ensuring that the full dosage of the drugwill be delivered.

FIG. 24 shows a cross-sectional view of manual activation assembly 163along line A-A. The activation assembly 163 includes a spring loadedstart button 164 which is slidably received within a button channel 165.The button 164 is maintained in an outward position by means of ahelical spring 166, located and supported in the button channel 165. Thehelical spring 166 is loaded both axially and torsionally within thebutton channel 165. FIG. 25 is a cross-sectional view of the activationassembly along line B-B, which shows a pin 169 which moves within agroove 170 in the button channel 165 from a first, pre-operationalposition [shown as position 169A], to a second, operational position[169B], to a third, locked position [169C].

Returning to FIG. 24, the button 164 has a finger 167 extendingtherefrom. The finger 167 is located directly above a deflectableelectrical contact 168. When the button 164 is depressed, the finger 167contacts the electrical contact 168 and causes it to deflect, thuscausing electrical communication between the contacts and initiatingoperation of the device 120.

In operation, the embodiment 120, shown in FIG. 22, is supplied with adrug cartridge 122. The cartridge 122, filled with drug 123 is fullyinserted into the cartridge recess 151. When the cartridge 122 is fullyinserted, the lip 153 of the sleeve 152 lockably engages with the shelf155 and prevents the cartridge 122 from being removed. As the cartridge122 is inserted, the needle sterility cover 127 engages with the pistonouter recess 126, and the tip of the needle pierces the needle sterilitycover 127 and piston 125 and moves into the interior of the cartridge,as shown in FIG. 23. The travel of the cartridge ends when the sleevelip engages with the shelf and the inner and outer edges of the channel.As the cartridge is fully inserted, the cartridge edge contacts thearched portion of the channel 156 causing it to deflect away from thecartridge. Such deflection applies pressure to the depressable buttonwhich depresses and pierces the container of chemical used to generatethe gas within the electrolytic cells. The device 120 is then applied bythe user or health care worker to the skin.

The device is then activated when the start button 164 is depressedcausing the finger 167 to contact the electrical contact 168 thusclosing an electrical circuit which initiates gas generation in thesub-assembly. Once the button 164 is depressed, the torsional force ofthe helical spring 166 prevents the button from springing back up andlocks the button, and second needle 134 in position [169B] duringoperation, as shown in FIG. 25.

When the cells 145, 146 are activated with electrical energy from thebatteries 150, both cells begin to generate gas. The first cell 145builds pressure quickly because of the low permeability of the firstdiaphragm 147, as shown in FIG. 26A. However, pressure is releasedthrough the hose and exits into the atmosphere within the housing 121.As pressure builds in the second cell 146, the second diaphragm 148deforms outwardly, closing the gap 143 between the hose and the topsurface of the second cell, as shown in FIG. 26B. When this is closed,the gas from the first cell can no longer escape into the atmosphere,causing the first diaphragm to elastically deform outwardly. Thisdeformation applies pressure to the lever 140, as shown in FIG. 26C.When pressure is applied on the lever, it causes the leaf spring to movefrom a first stepped increment 138A to a second increment 138B. Thismovement causes the piston 125 to move further along the length of thedrug cartridge 122, decreasing the volume of drug 123 in the cartridgeand moving such drug into the patient via the needle 124.

Once pressure has built sufficiently in the first cell 145 so as to movethe leaf spring incrementally forward, gas generation in the cells isdeactivated so as to begin to decrease pressure within the cells. As thepressure in the second cell decreases, the second diaphragm flattensout, thereby re-creating the gap 143 and allowing air to bleed quicklyfrom the first cell, as shown in FIG. 26D.

The gas-generation sub-assembly is designed in such a way so as toprovide maximum efficiency in the cycle of moving the leaf spring from afirst increment 138A to a second increment 138B. The low permeability ofthe first diaphragm 147 allows the pressure to build in the first cell145 and thus results in quick deformation of the diaphragm and movementof the reciprocating piston 143. However, the integration between thefirst and second cells, 145, 146, is important in order to quicklyrelease the pressure within the first cell 145 after the leaf spring hasbeen moved forward. The hose 149 between the first and second cellconnects the two cells during deflection and provides first for thebuild up of pressure. After the pressure within the first cell buildssufficiently move the reciprocating piston, the electrical connection tothe batteries 150 is disconnected, or decreased. This causes a rapiddecrease in the pressure of the second cell 146 because much of the gascreated escapes through the second diaphragm. As the pressure in thesecond cell 146 declines, the second diaphragm looses height andrecreates the gap 143, thus allowing gas from the first cell to quicklybleed off and return to a low pressure state to begin the next cycle. Itshould be noted that it is possible to maintain a minimum current levelwithin the cells in order to keep a minimum level of pressure in thecells so as not to start the build up of pressure from a lower pointthan necessary, thus maximizing the efficiency of the cycle time. In oneapplication, the current needed during the gas generation portion of thecycle may range from 5-7 milliampers, and the current to maintain theminimum level of pressure may range from 30-50 microampers. This celldesign has enabled the cycle time to decrease from 20 minutes to 5minutes in the present embodiment.

The length between activating and deactivating the electrolytic cellsmay be controlled by means of a microprocessor, along with the use ofdifferent diaphragm materials. Thus, the cycle time to move the leafspring a single increment may be adjusted depending upon the deliveryrate desired. Moreover, the number and size of increments may be alteredto provide further flexibility in the delivery rate.

When the delivery is complete, the helical spring 166 which istorsionally loaded, forces the pin 169 to move from the operationposition [169B] to a locked post-operational position [169C]. Thiscauses the entire activation assembly to retract and the exterior end136 of the second needle 134 to be recessed into the housing, therebyavoiding any accidental injury or attempted further use of the device120.

It should also be noted that in the present embodiment 120, the numberof sterile components has been minimized so as to eliminate the need tosterilize the entire device. The following components are sterilized asan assembly prior to being assembled into the device. The sterilizedsub-assembly includes the needle sterility cover 127, the needle 124,the tubing 130, the start button 164, the drug pathway 133, the secondneedle 134, and the penetrating needle sterility protector 135.

It will be appreciated that the embodiments discussed above arepreferred embodiments, falling within the scope of the appended claims,and that various alternative embodiments are contemplated. For example,while leaf and coil springs were discussed in the preferred embodiments,it is anticipated that other types of springs may also be used.

The term “drug” used herein includes but is not limited to peptides orproteins, hormones, analgesics, anti-migraine agents, anti-coagulantagents, narcotic antagonists, chelating agents, anti-anginal agents,chemotherapy agents, sedatives, anti-neoplastics, prostaglandins,antidiuretic agents, anti-sense agents, oligonucleotides, mucosalvaccines, gene-based medicines and permeability and enhancing agents.

Typical drugs include peptides, proteins or hormones such as insulin,calcitonin, calcitonin gene regulating protein, atrial natriureticprotein, colony stimulating factor, betaseron, erythropoietin (EPO),interferons such as α, β or γ interferon, somatropin, somatotropin,somastostatin, insulin-like growth factor (somatomedins), luteinizinghormone releasing hormone (LHRH), tissue plasminogen activator (TPA),growth hormone releasing hormone (GHRH), oxytocin, estradiol, growthhormones, leuprolide acetate, factor VIII, interleukins such asinterleukin-2, and analogues thereof; analgesics such as fentanyl,sufentanil, butorphanol, buprenorphine, levorphanol, morphine,hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine,bupivacaine, diclofenac, naproxen, paverin, and analogues thereof;anti-migraine agents such as sumatriptan, ergot alkaloids, and analoguestherof; anti-coagulant agents such as heparin, hirudin, and anloguestherof; anti-emetic agents such as scopolamine, ondansetron,domperidone, metoclopramide, and analogues thereof; cardiovascularagents, anti-hypertensive agents and vasodilators such as diltiazem,clonidine, nifedipine, verapamil, isosorbide-5-mononitrate, organicnitrates, agents used in treatment of heart disorders, and analoguesthereof; sedatives such as benzodiazepines, phenothiozines, andanalogues thereof; chelating agents such as deferoxamine, and analoguesthereof; anti-diuretic agents such as desmopressin, vasopressin, andanalogues thereof; anti-anginal agents such as nitroglycerine, andanalogues thereof; anti-neoplastics such as fluorouracil, bleomycin, andanalogues thereof; prostaglandins and analogues thereof; andchemotherapy agents such as vincristine, and analogues thereof.

Other drugs include antiulcer agents, such as but not limited tocimetidine, and ranitidine; antibiotics; anticonvulsants;antiinflammatories; antifungals; antipsychotics; corticosteroids;immunosuppressants; electrolytes; nutritional agents and vitamins;general anesthetics; antianxiety agents, such as but not limited tocompazine; and diagnostic agents.

1-32. (canceled)
 33. A drug delivery device comprising: (a) a housingcontaining a drug reservoir; (b) a slidable piston operable to expeldrug from the drug reservoir; (c) a ratchet mechanism in communicationwith the piston, the mechanism being operable to undergo incrementaladvancement and thereby to drive the drug from the reservoir in a seriesof fixed increments; (d) a member operatively associated with themechanism to cause the incremental advancement of the mechanism as themember moves in a first direction; and (e) a gas generator locatedwithin the housing and operable to generate gas to expand a chamber, themember being in transmission relation to the chamber, whereby the memberis driven by the movement of the chamber to advance the mechanism andthereby drive the drug from the reservoir in the series of fixedincrements, each of the fixed increments corresponding to a respectiveadvancement of the mechanism; wherein the ratchet mechanism comprises aflexible ratchet element which is sufficiently stiff to drive medicamentfrom the chamber when driven by the member and sufficiently flexible tobe bent before it meets the member, whereby the overall length of thedevice is reduced relative to a device in which a rigid ratchet elementprotrudes linearly from the mechanism before use.
 34. The drug deliverydevice according to claim 33, wherein the mechanism comprises two ormore co-operating flexible ratchet elements which are individuallysufficiently flexible to be bent before they meet the member but whenjoined together are together sufficiently stiff to drive medicament fromthe chamber when driven by the member.
 35. The drug delivery deviceaccording to claim 34, wherein the two or more co-operating flexibleratchet elements are bent away from one another before they meet themember. 36-55. (canceled)